Project Summary Uveitis is one of the leading causes of acquired blindness. Uveitis can be subdivided based on the anatomic portion of the uvea that is affected; 85% of uveitis is predominantly anterior. Since HLA B27 is associated with 50% of the patients who develop acute anterior uveitis, HLA B27 related acute anterior uveitis is easily the most common phenotype of uveitis. Despite HLA B7?s remarkable role in contributing to the pathogenesis of uveitis, the mechanism that explains this effect is unknown. Using a rat model, we have recently reported that HLA B27 shapes the microbiome, the microbial cells that co-habit the human body. Furthermore, we note that specific gut bacteria including Candidatus arthromatus are coated with IgA in the rat model. In addition, bacteria in the rat model are translocated from the gut to the joint. Importantly we have extrapolated these observations to patients by showing that HLA B27 shapes the microbiome in people and that IgA coated bacteria are more prevalent in B27+ subjects relative to controls. We hypothesize that the microbiome is causally related to B27-related acute anterior uveitis. We further hypothesize that intestinal bacteria are translocated to sites of inflammation such as the uvea. We propose 3 aims to test these hypotheses. These studies represent an innovative approach to understand the pathogenesis of HLA B27-related disease, a goal which has been elusive for 43 years despite the strength of the association.